Abstract
Simple SummaryPerineural invasion is a complicated process involving a series of cells and extracellular matrix components in the tumor microenvironment, particularly the crosstalk between cancer cells and neurons. Perineural invasion occurs in many malignant tumors, including gastric carcinoma, biliary tract tumor and pancreatic cancer. It is identified in approximately 80–100% of pancreatic cancer patients and is correlated with poor survival and decreased quality of life. Extensive studies have revealed the subtle molecule regulatory mechanisms during perineural invasion, as well as the potential causal link with pancreatic cancer-associated pain. Here, we introduce the underlying mechanism of perineural invasion and its possible relationship with the intractable pain in pancreatic cancer patients.Pancreatic ductal adenocarcinoma (PDAC) is one of the cancers with the highest incidence of perineural invasion (PNI), which often indicates a poor prognosis. Aggressive tumor cells invade nerves, causing neurogenic inflammation; the tumor microenvironment also induces nerves to undergo a series of structural and functional reprogramming. In turn, neurons and the surrounding glial cells promote the development of pancreatic cancer through autocrine and/or paracrine signaling. In addition, hyperalgesia in PDAC patients implies alterations of pain transmission in the peripheral and central nervous systems. Currently, the studies on this topic are relatively limited. This review will elaborate on the mechanisms of tumor–neural interactions and its possible relationship with pain from several aspects that have been focused on in recent years.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant tumors with a five-year survival rate of less than 10% [1,2]
As more and more clinical studies have shown that perineural invasion (PNI) is related to poor prognosis [4], the role of nerves in pancreatic cancer has attracted widespread attention over the last few years
The expression of muscarinic acetylcholine receptor 3 is significantly correlated with high grade, more lymph node metastasis, and shorter overall survival of PDAC patients [90]
Summary
PDAC is one of the most lethal malignant tumors with a five-year survival rate of less than 10% [1,2]. PNI, a phenomenon defined as cancer cells that surround more than 1/3 of the nerve periphery or invade any layer of the neurolemma [3], occurs in approximately 80–100% of the affected individuals and has become one of the most outstanding clinical features of pancreatic cancer [4]. As more and more clinical studies have shown that PNI is related to poor prognosis [4], the role of nerves in pancreatic cancer has attracted widespread attention over the last few years. As the basis of PNI, the innervation in PDAC has been confirmed, including sensory and autonomic nerves. The tumor microenvironment and cancer cells of PDAC influence the nervous system in several aspects. Cancer cells directly contact the nerve cells, promoting the development of neurogenic inflammation in PDAC. The nerve invasion eventually becomes one of the primary sources of PDAC-related pain
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